Chewing gums and method of manufacturing the same

ABSTRACT

Chewing gums are obtained by entrapping a liquid within a mass of gum, blast freezing the gum and the entrapped liquid, and increasing the temperature of the gum to just below the melting point of the liquid, causing the liquid crystals to anneal. By manipulating the size and/or morphology of the frozen liquid crystals, one can thereby manipulate the internal structure of the gum. Optionally, the liquid can contain a drug in solution. If the solvent is then removed, the drug is left in the interstices of the gum. The rate of release of the drug from the gum is thus determined by the distribution of the drug within the gum arising from the annealing step. This method of manufacturing a chewing gum avoids the use of elevated temperatures, and is thus particularly suitable for entrapping thermolabile substances.

TECHNICAL FIELD

[0001] This invention relates to chewing gums and in particular to theiruse in the delivery of active ingredients, including liquid solutions ofactive ingredients, thermolabile active ingredients in solid or liquidform and homeopathic medicines.

BACKGROUND ART

[0002] The use of chewing gum as a drug delivery vehicle is well knownand under extensive investigation by many researchers (see, for example,“Chewing gum as a drug delivery system”, Margrethe Romer Rassing,Advanced Drug Delivery Reviews, 13, 89-121 (1994)). Apart from the factthat chewing gum offers a convenient and easily used vehicle for activeingredient administration, it presents additional features ofpharmacological importance including the fact that absorption of activeingredients through the oral mucosa avoids hepatic first passmetabolism, and may therefore offer an opportunity to reduce therapeuticdose requirements.

[0003] The primary disadvantage of chewing gum is a difficulty inregulating the total dose administered. In many cases it is impossibleto formulate gum such that the total dose contained is released and madeavailable for absorption.

[0004] While buccal absorption of active ingredients avoids livermetabolism, the act of chewing produces saliva which necessitatesswallowing and there is no way of regulating the amount of activeingredient which is swallowed and the amount absorbed through the buccalmucosa. Furthermore, active ingredients which are poorly water-solubleare not easily absorbed when present in chewing gum in solid form.

[0005] Another problem is thermal stability: the industry standardmethod of formulating any chewing gum involves a hot melt process inwhich the temperature of the gum base (to which active ingredients,flavours and excipients are added as a dry powder) may be of the orderof 80° C. Thermolabile active ingredients are denatured by the highprocessing temperatures and thus cannot be formulated for delivery usingthe industry standard process technology.

[0006] A solution to this problem has been proposed which avoids thehigh temperatures of the hot melt process. By freezing the gum it can becomminuted by grinding, and then an active ingredient can be added inpowdered form. The mixture of powdered active ingredient and frozen gumparticles can be compressed together and thawed. Processes of this typeare disclosed in: U.S. Pat. No. 4,000,321, U.S. Pat. No. 4,161,544 andU.S. Pat. No. 4,737,366.

[0007] WO 96/03111 discloses details of comminution of gum to a powderedform followed by blending with liquid ingredients, before compression tothe form of tablets which are then subsequently dried by hot air.

[0008] Despite the disadvantages, there are many suitable activeingredient candidates some of which are already available in the marketin chewing gum form. These active ingredients include nicotine,anti-microbials for local oral infection, fluoride gums for preventionof dental caries, vitamins and some functional foods. The common featureof all commercial products is that they are intended for local oralapplication of the active ingredient and, like ointments or otherconventional topical medicaments, the total dose administered is notcritical to the therapeutic value.

[0009] The delivery of liquids presents its own problems, particularlywhere aqueous solutions are involved. A major problem in entrappingwater in chewing gums is that water (and liquids such as water/ethanolsolutions which are often used as a base for homeopathic dilutions) arenot compatible with conventional chewing gum processing. There is nopoint in enclosing a discrete volume of water en masse in a gum envelopebecause the volume bursts out in the first bite. So a problem exists infinding some way of dispersing the aqueous solution in the gum such thatit is released slowly over a period of about twenty minutes, withoutsubjecting the active ingredient to some incompatible conditions such asextreme heat, shearing, electromagnetic forces or chemical manipulation.

[0010] If a liquid must be encapsulated, other methods can be used, suchas using a resin which holds a polar liquid therein by charge attraction(such as the nicotine gums marketed by Kabi Pharmacia as “Nicorette”);or the liquid can be encapsulated in liposomes (also referred to asnanospheres/microspheres depending on size) and these particles can beentrapped in a gum in much the same way as with a powder. The use of“micro-sponges”, containing encapsulated liquids is disclosed in U.S.Pat. No. 5,154,927. Using these methods the total volume of liquid whichcan be encapsulated is very small, being approximately 0.1 ml for astandard sized piece of gum.

[0011] The present invention aims to provide gums in which significantlymore liquid (e.g. up to 1.0 ml or more) can be formulated in each pieceof gum.

[0012] Therefore, it is an object of this invention to provide a chewinggum product giving improved sustained release of active ingredients andone which is particularly suitable for thermolabile biologicalingredients and other medicaments some of which may be required to be inliquid solution.

DISCLOSURE OF INVENTION

[0013] The invention provides a method of manufacturing a chewing gumcomprising the steps of:

[0014] a) entrapping a liquid within a mass of gum;

[0015] b) cooling the gum by an amount sufficient to freeze theentrapped liquid and thereby form entrapped frozen liquid crystalswithin the gum; and

[0016] c) regulating the temperature of the gun so as to manipulate thesize and/or morphology of the frozen liquid crystals, and therebymanipulate the internal structure of the gum to provide a gum havingspaces therein of a plate-like or sheet-like shape.

[0017] It has been found that by controlling the size and/or morphologyof the frozen crystals inside the gum matrix it is possible to obtaingood control of the internal spaces inside the gum. The distribution ofan active ingredient in the liquid is thus controllable, and this has asignificant impact on the release characteristics of the gum.

[0018] Preferably, step a) comprises comminuting the gum to aparticulate form and adding the liquid thereto.

[0019] The liquid can thus act as a binder for the particulate gum. Theliquid may be an active ingredient in itself, or it may contain anactive ingredient (or a flavouring) in solution, suspension orhomeopathic dilution. Alternatively, a simple liquid such as water maybe added simply in order to use the frozen crystals of water to controlthe internal structure of the gum. If the water is subsequently removed,one is left with “blanks” which are adapted to absorb a liquid in theinternal spaces vacated by the water.

[0020] Preferably, the comminution of the gum is achieved by a processselected from jet milling, homogenisation in a suspending liquid, andcryogenic milling.

[0021] The operation of a jet mill is well known to those skilled in theart. In jet milling, particle size reduction occurs from collisionsbetween particles driven at high speeds by cold nitrogen gas. As astarting material, commercially available gum base is supplied inparticulate form of a size suitable for feeding into a jet mill.Particles whose size is sufficiently reduced exit the mill chamberautomatically.

[0022] In homogenisation in a suspending liquid, pieces of gum aresuspended in a liquid such as a saturated aqueous salt solution. Acommercially available homogeniser is used to reduce the gum particlesto an extremely fine suspension. The operation occurs at a suitably lowtemperature to allow the gum to be effectively chopped. As analternative to a salt solution, any liquid having a low enough freezingpoint may be used.

[0023] In cryogenic milling, the gum is frozen and ground to a suitablesize by any known method of comminuting a brittle mass.

[0024] Alternatively, step a) may comprise melting the gum, adding aliquid thereto, and forming an emulsion of the liquid in the melted gum.

[0025] This method is less preferred as it is unsuitable for substanceswhich are denatured at high temperatures. However, it may be suitablefor robust ingredients, or for simple liquids such as water when wateris added on its own.

[0026] Preferably, step b) comprises blast freezing the gum to a solidstate.

[0027] Blast freezing is rapid freezing obtained by creating the maximumtemperature differential between the unfrozen mass and a freezingsurface, thereby achieving the maximum heat flow rate from the freezingmass. When the liquid contains an active ingredient in solution, blastfreezing tends to cause the water and solute molecules to take up a muchsmaller crystal secure relative to those that would be present iffreezing was effected at slower rates. The initially smaller crystalstructures allow room for more crystal growth when the temperature isvaried during annealing (as described below). This in turn allows thewater/gum matrix to be better compacted during ice annealing.

[0028] Suitably, the gum is frozen to a temperature which is more than10° C. below the freezing point of said liquid.

[0029] Preferably, step c) comprises regulating the temperature of thegum while maintaining the liquid in frozen form.

[0030] In particularly preferred embodiments, step c) comprises bringingthe gum to a temperature at which the crystals undergo annealing.

[0031] During annealing, the frozen crystals grow and bond with oneanother. In so doing, they generate pressure at the interface with thegum, compressing the pieces of gum together (when the gum has beenformed by adhering comminuted gum particles together).

[0032] The structure of the crystals generated by annealing determinesthe distribution of the liquid within the gum. In particular when theliquid comprises water, the ice crystals tend to anneal into sheet-likeor plate-like structures which subsequently provide a sustained releaseof an ingredient contained in the spaces formed during annealing.

[0033] Preferably, the annealing temperature to which the gum is broughtin step c) is sufficiently warm to cause the gum to exhibit plasticitywithout allowing the liquid to melt.

[0034] At such temperatures, the plasticity of the gum facilitates thecrystals annealing together and enables the Act of the gum matrix to bemanipulated, which in tam influences the release characteristics of thegum during chewing.

[0035] Further, preferably, the temperature to which the gum is broughtin step c) is within 5° C. of the melting point of the frozen liquid.

[0036] Suitably, the gum is maintained at an annealing temperature fornot less than 2 hours.

[0037] The process of crystal growth during annealing is relativelyslow, and the morphology of the crystals is thus determined both by theannealing tempera and the duration of the annealing step.

[0038] In certain embodiments, step c) comprises thawing the liquid andre-freezing the liquid at least once, more preferably at least threetimes.

[0039] This can be referred to as “freeze-thaw texturising” the gum. Theindividual particles of gum are compressed together with a relativelylarge force arising from the advancing ice front as the liquid freezes.Repetition of the freeze-thaw cycle gives rise to a gum having a goodconsistency, and indeed allows the consistency to be accuratelycontrolled.

[0040] In preferred embodiments, the method further comprises the stepof:

[0041] d) removing the liquid from the gum after step c).

[0042] In particular, unless it is important for the liquid to beactually present in the finished gum, the preferred finished productwill generally be a dry gum. In particular, removal of the liquid willleave behind any suspended or dissolved ingredients, thereby providing agum in which these ingredients are incorporated within spaces whose sizeand shape has been determined by the aforementioned temperature control.

[0043] If no ingredient is entrapped, then the removal of liquidprovides “blanks” of gum which arm adapted to absorb a liquid into thespaces vacated during removal of the original liquid. Even if no otherliquid is absorbed by the blanks, the texture of the gum will bedifferent from conventional gums, since the gum will be interlaced withinternal spaces. Thus, a gum is provided which may be advantageous inand of itself, without any emphasis on the delivery characteristics orany entrapped ingredients. From the point of view of manufacturers, suchgums utilise fewer ingredients for a given size piece of gum (i.e. agiven volume), because much of the internal volume of the gum is filledwith air (or another gaseous substance if desired).

[0044] Preferably, step d) comprises subjecting the gum tovacuum-assisted freeze drying.

[0045] Freeze drying enables the liquid to be extracted from the gummatrix while leaving the spaces originally occupied by the frozen liquidsubstantially intact. In general, the removal of liquid by freeze dryingopens channels from the internal frozen crystals to the surface of thegum. These channels can be re-sealed by coating the gum or by lightcompression of the ace of the gum.

[0046] In preferred embodiments, the liquid comprises a solvent in whicha solute has been dissolved, and the solvent is removed to leave thesolute entrapped in the gum.

[0047] In alternative embodiments, the method further comprises the stepof:

[0048] d′) sealing the gum with the liquid intact either before or afterthawing the gum.

[0049] This is most suitable when the gum is to be used to deliver aliquid per se, such as a liquid active ingredient or a homeopathicdilution. The volume of liquid entrapped using this method issubstantially greater than in prior art methods of entrapping a liquidin a gum.

[0050] According to the invention it is possible to get the powdered gumto absorb about 40% of its own weight without feeling wet. The loadedgum can be pressed into a tablet shape and then dipped into molten gumto form a seal. The sustained release characteristics of the gum can beenhanced, by freezing, thawing and re-freezing the loaded gum. The endresult is a piece of gum consisting of a gum envelope, enclosing acompressed powdered gum matrix, with a water-based solution in theinter-particulate spaces. As an alternative to dipping the loaded piecesof gum in a molten coating, it is possible to seal the porous surface ofthe compressed gum granules after the liquid active ingredient has benabsorbed. For example one ca use brief contact with a hot metal surfaceto seal the gum pieces.

[0051] In a further modification of the method according to theinvention the gum is mechanically compressed dung steps b) and c).

[0052] External mechanical compression adds to the internal pressure Agenerated by ice annealing, and further adds to the integrity of thefinished pieces of gum.

[0053] Suitably, the liquid added in step a) contains a thermolabilesubstance.

[0054] As indicated above, the invention is particularly suitable forsuch substances as it allows a gum to be prepared while avoiding the useof any elevated temperatures. Thermolabile substances are denatured atunsuitable temperatures, including many biologically importantsubstances, particularly proteins such as enzymes, antibodies andhormones.

[0055] Suitably, the liquid added in step a) comprises a homeopathicpreparation.

[0056] Homeopathic preparations are made by successive dilutions of anactive ingredient, to a pint (in many cases) where one would expect nomolecules of active ingredient to remain in an average sample. Suchmedicines are widely used, and are generally administered as a liquid oras a lactose pillule which has absorbed the liquid. The presentinvention provides for the first time a method of incorporating anactive ingredient in aqueous form in a finished sustained release gumwithout subjecting the liquid to elevated temperatures.

[0057] A particularly advantageous application of chewing gum preparedaccording to the invention is in the area of oral medicine. In oralhealthcare there are many clinical indications which would benefit fromsustained delivery of therapeutic products from chewing gum, examples ofthese would include xerostomia (dry mouth syndrome), oral thrush, dentalcaries, gingivitis, periodontitis and mouth ulcers.

[0058] There are many conventional medicines available in differentformulations designed to treat these conditions. The application ofchewing gum preparations is more advantageous when long-termprophylactic use is desired. Many conventional medicines are unsuitablefor prophylactic applications due to long-term side effects. Manybiological preparations, which would provide long-term prophylaxis, archeat sensitive and are not easily incorporated into chewing gum usingthe industry standard process.

[0059] Suitably, the liquid added in step a) contains one or morepurified constituents of egg.

[0060] For example, Irish Patent Specification No. 65218 describes amethod of developing hyper-immune egg yolk antibodies against theorganisms causing oral thrush, and the contents of this patentspecification are incorporated herein by reference. Thus, eggimmunoglobulin may be used to replicate the constituents of saliva. Itis equally feasible to develop antibodies against any oral pathogen, andto combine these with other constituents of egg such as lysosyme toeffectively mimic the protective effect of human saliva which will havewide ranging prophylactic applications in oral medicine.

[0061] Accordingly, in preferred embodiments the liquid added in step a)contains one or more constituents having biological activitycharacteristic of human saliva.

[0062] Patients suffering from xerostomia arc not only disadvantaged bythe discomfort and difficulty of having a dry mouth. Because of theimmune activity of saliva, such patients are also highly susceptible tooral infection, which makes the incorporation of immune constituents ina gum particularly advantageous.

[0063] Suitably, the liquid added in step a) contains a herbal extract.In preferred embodiments, the herbal extract is Vaccinium myrtilis orMelissa officianalis.

[0064]Vaccinium myrtilis is known to have vasoprotective properties inoral applications (see Morazzoi & Bombardelli, Fitoterapia; LXVII, No.1, 1996). Similarly the extract of Melissa officianalis is known to havetherapeutic properties in viral ulceration of the mouth (see Wolbling &Leonhardt, Phytomedicine. 1, 25-31(1994)).

[0065] In another aspect, the invention provides a chewing gumcomprising a gum matrix having spaces within the gum mat, characterisedin that the size and/or morphology of the spaces is determined duringthe manufacture of the gum by a change in the size and/or morphology ofcrystals of an entrapped frozen liquid present during manufacture, andin that the spaces have a plate-like or sheet-like shape due to theformation and growth of ice crystals during manufacture.

[0066] Such gums provide for a controlled and sustained release ofactive ingredient, and as indicated above, they able a significantlyhigher dose load to be included (up to 1 ml liquid per 3.1 g piece ofgum, as opposed to approximately 0.1 ml in the prior art).

[0067] As previously described, in certain embodiments the entrappedfrozen liquid present during manufacture has been removed from thefinished product.

[0068] This provides a gum having a “honeycomb” of internal spaces whichgive the gum a lighter consistency and an improved mouthfeel.

[0069] Preferably, the spaces in the finished product contain a residualmaterial originally dissolved or suspended in said liquid.

[0070] In alternative embodiments, the spaces in the finished productcontain said liquid in thawed form.

[0071] Preferably, the spaces are of an average size greater than theaverage maximum size of individual liquid volumes which can beincorporated in a gum matrix, due to the use of an annealing step whichencourages crystal growth between adjacent crystal structures.

[0072] Thus, while only relatively small crystals may be formed duringthe initial freezing of the gum, annealing enables larger volumes toform by adjacent crystals annealing together.

[0073] Preferably, the entrapped frozen liquid present duringmanufacture is a liquid of a type hereinbefore defined.

[0074] A further method of entrapping the liquid in the gum is bycreating an emulsion of aqueous drug in a gel of gum base in hexane orcyclohexane or similar suitable solvent The morphology of the disperseddrug can be fixed by rapid freezing of the emulsion and evaporation ofthe solvent to dept gum on the frozen droplets of drug. The resultingparticles can then be compressed together to obtain a mass of gum havingan entrapped liquid, and this mass can then be subjected to freeze-thawtexturising as described herein. Similarly, particles ofliquid-containing gum can be obtained by vacuum-assisted cryogenicspheronisation of drug in a polymer, as described in WO-A95/22036, thecontents of which are incorporated herein by reference.

BRIEF DESCRIPTION OF DRAWINGS

[0075] The invention will be further illustrated by the followingdescription of embodiments thereof, given by way of example only withreference to the accompanying drawings, in which:

[0076]FIG. 1 is a representation of a cross-section of a gum preparedfrom a powdered gum base and a dye, using a hot melt process;

[0077]FIG. 2 is a representation of a cross-section of a gum preparedfrom a powdered gum base and a dye, using a dry powder compressionprocess;

[0078]FIG. 3 is a representation of a cross-section of a gum prepared byadding a solution of dye to a powdered gum base;

[0079]FIG. 4 is a representation of a cross-section of a gum preparedfrom a powdered gum base and a solution of dye, using a freeze-thawtexturising process according to the invention;

[0080]FIG. 5 is a representation of a cross-section of a gum preparedfrom a powdered gum base and a solution of dye, using an ice annealingprocess according to the invention; and

[0081]FIG. 6 is a comparative graph illustrating the different releaserates over time for gums prepared according to Examples 2 and 6,respectively, but with the dye replaced by lysosyme.

MODES FOR CARRYING OUT THE INVENTION EXAMPLE 1

[0082] Preparation of Gum Powder

[0083] A standard confectionery gum base (free of flavours andcolourings) was used as the starting material for the preparation of agum powder. Three different methods were used, each of which will bedescribed in turn. Later Examples demonstrate the formulation of thepowder in finished chewing gums.

[0084] A: Jet Milling

[0085] Finely chopped pieces of gum (approximately 10 mm cubes) werechilled to −10° C. in a freezer and fed into the hopper of a jet-mill.The mill was driven by nitrogen gas at −70° C. and particle sizereduction was achieved by collision in the mill. Particles which weresufficiently reduced in size were entrained in the stream of gas andexited the mill chamber to be recollected in a cyclone apparatus.Recovered particles averaged 50 μm in size (as measured by microscopy).

[0086] B: Cryogenic Milling

[0087] Finely chopped pieces of gum at room temperature were placed in aporcelain mortar and liquid nitrogen was poured on top of them, (themortar was pre-frozen to −20° C. as the sudden freezing effect of liquidnitrogen could cause a warm mortar to break or even explode). When thenitrogen had boiled off the brittle gum pieces were easily ground with apestle to a fine powder, this was allowed to come to room temperature.The powder was shown to absorb water to about 40% by weight.

[0088] C: Homogenisation

[0089] Chopped pieces of gum were suspended in a saturated salt solutionat −5° C. An “Ultra-Turax” (Trade Mark) high speed homogeniser was usedto chop the gum pieces to an extremely fine suspension. The suspensionwas filtered under vacuum and the filtrate re-suspended in water andre-filtered to remove residual salt. The wet filtrate was dried byevaporation at room temperature and further drying effected in adesiccator.

[0090] As a useful variation on this process one can leave some salt (orany other hygroscopic substance) in the dried matrix as it considerablyimproves re-absorption of aqueous active ingredient (provided that thesalt and the aqueous active ingredient are compatible).

[0091] A suitable alternative to saturated salt is a 50% ethanol:watersolution, or glycerol, or any other liquid medium which will not freezeat the reduced temperatures necessary to homogenise the gum solution.Homogenisation may be improved at temperatures of −20° C. or less.

EXAMPLE 2

[0092] Replication of Industry Standard Hot Melt Process (ComparisonExample Only).

[0093] Red food dye (cochineal) as a dry powder was added to thepowdered gum base (prepared according to Example 1A) in an amount of 10%w/w and mixed at 60° C. The molten mixture was spread onto a coolsurface and allowed to set at room temperature. Superficially the gumhad an intense red colour. The mass was chilled in a refrigerator andbroken. The fractured surface was examined under magnification, it wasapparent that the dye was dispersed as discrete particles in a uniformgum structure. A representation of the fractured surface is provided inFIG. 1.

EXAMPLE 3

[0094] Replication of Dry Powder Compression Process (Comparison ExampleOnly).

[0095] A 10% w/w mixture of cochineal in powdered gum (preparedaccording to Example 1A) was blended thoroughly. The mixture wascompressed into a slab at room temperature. The slab of thus preparedgum was again chilled in a refrigerator and broken. The fracturedsurface was again examined under magnification, and in this case the reddye was visible as particles coating discrete pieces of the powderedgum. A representation of the fractured surface is provided in FIG. 2.

EXAMPLE 4

[0096] Formulation of Powdered Gum With Liquid Solution (ComparisonExample Only).

[0097] A paste was prepared from the powdered gum of Example 1A byadding a 5% w/v aqueous solution of cochineal in an amount of 10% v/w(0.1 ml solution per 1 g gum). The paste was malleable and relativelyeasily worked into a slab, by compression between a roller and a surfaceat room temperature. The cooled slab was cut into individual piecesusing a cheese-wire.

[0098] The individual pieces felt damp but retained their form. Ifpieces were placed on blotting paper the dye solution soaked out of thegum pieces into the paper.

[0099] Individual pieces were coated with molten gum base and allowed tocool. The coated pieces were sliced through with a cheese-wire andexamined under magnification. The red dye solution was clearly visibleas a thin film coating each piece of the aggregate powder. Arepresentation of the fractured surface is provided in FIG. 3.

EXAMPLE 5

[0100] Formulation of Gum According to the Invention Using Freeze-ThawCycle

[0101] Pieces of gum containing an entrapped liquid solution wereprepared according to Example 4.

[0102] The gum pieces were placed on a steel tray in a deep freeze at−20° C. for four hours before being removed and allowed to equilibrateat room temperature for 4 hours. The process of freeze-thaw cycling wasrepeated four times and then the pieces were sliced through with acheese-wire.

[0103] The consistency of the gum matrix had obviously changed as asmall amount of dye seeped from the cut surface immediately but furtheramounts could not be desorbed from the cut surface even by placing thecut section on blotting paper. This indicates that the liquid has forthe most part been retained in the gum matrix and thus that a stable gumcontaining an aqueous solution can be obtained by effecting changes inthe morphology of the interstitial liquid-containing spaces in the gummatrix. These changes are brought about by the successive growths of icecrystals during successive freeze-thaw cycles.

[0104] Under magnification the cut surface had a honey-comb or spongelike appearance with dye seemingly trapped in the capillary like matrix:A representation of the cut surface is provided in FIG. 4.

[0105] The finished pieces were coated by dipping in a molten gum bath.Alternative coatings which seal in the entrapped liquid can includeshellac, gelatine or gum tragacanth.

EXAMPLE 6

[0106] Formulation of Gum According to the Invention Using Ice Annealing

[0107] Pieces of gum containing an entrapped liquid solution wereprepared according to Example 4.

[0108] The gum pieces were refrigerated to −20° C. and then brought upto −5° C. and held at that temperature for 24 hours to allowice-annealing to take place. At −5° C. the gum base granules are stillrelatively plastic in so far as it is possible to distort them underpressure. At −5° C. or thereabouts, the liquid solution was just belowits melting, and at this temperature ice crystals grow and re-annealwithin the gum matrix.

[0109] The process of ice-crystal growth causes substantial pressure todevelop at the interface between the ice and the gum and in so doingforces the pieces of gum together, causing them to take up aninterconnected lattice structure surrounding the enlarged ice crystalswhich tend to form sheets during the annealing process. The temperaturecan be varied for other solutions; in general optimum annealing isachieved by holding the gum at a temperature just below the freezingpoint of the liquid.

[0110] After 24 hours the temperature was again reduced to −20° C. andlyophilisation or freeze-drying commenced. In order to control the rateof drying and the extent of “blowing” in the gum section, no externalheat (heating ramp) was used.

[0111] The shelves in the drier were maintained at −20° C. for 48 hours,after which secondary drying was effected at +20° C. for 12 hours. Thevacuum pressure maintained throughout this 60 hour period was 100millibars (10 kPa).

[0112] An initial scrutiny showed the gum pieces to have an open“woolly” texture, and they were more easily compressed than the othergums described in previous examples. This is considered to be due to theair spaces vacated by the liquid during lyophilisation.

[0113] Under magnification the cut sections of gum were observed to havea marbled appearance with the solute (red dye) deposited in marble-likestriations through the gum matrix. A representation of the cut surfaceis provided in FIG. 5.

[0114] The process of lyophilisation is well known to those skilled inthe art. A suitable review can be obtained in “Basic Principles offreeze-drying for pharmaceuticals”; A. P. MacKenzie, Bulletin of theParenteral Drug Association, 20, No. 4 (1966). In summary the processconsists of freezing a solution (or suspension) and establishing avacuum over the frozen material to effect sublimation (which may befacilitated by heating the frozen mass). The solvent is sublimed andrefrozen in a condenser operated at temperatures well below that of thesubliming frozen solvent.

[0115] Using lyophilisation and ice-annealing techniques on thehomogenised gum base it is possible to enhance the sustained releasecharacteristics of the final formulation thereby improving the use ofsuch material for oral drug delivery.

[0116] The ice annealing procedure can be used to create gum containingliquid active ingredient solutions, which can be retained in thefinished product or removed, suitably by lyophilisation. Whenlyophilisation occurs on a frozen active ingredient solution, the solute(i.e. the active ingredient) is deposited in the gum matrix. Such gummatrices contain dry active ingredient which is readily re-hydrated onchewing. A variation on this technique involves using a simple solventas the frozen liquid. When the liquid is removed, empty spaces are leftbehind, i.e. gum “blanks” are created which can be re-hydrated withliquid active ingredient solutions prior to chewing.

[0117] The formation of the gum lattice may be facilitated by trappingthe liquid paste between steel plates, thus increasing the compressioneffect during freezing and ice-annealing.

[0118] The effect of sublimation in the gum matrix is to cause channelsand fissures to open up in the drying mass permitting the escape ofwater vapour. These channels may be closed in by light compression ofthe dry matrix without affecting the structure of the formulated gum. Ifthe formulation is intended for absorption of liquid dose into the gumblanks, these fissures will be left open until after re-hydration hasbeen completed.

[0119] From the foregoing description it will be apparent to thoseskilled in the art that the size of the spaces in the gum matrix can bemanipulated using freeze-thaw texturising and/or ice annealing prior todrying. Rapid freezing with minimum ice-annealing will create smalldiscrete particles of ice which will blow fissures through the gum asthey dry (due to the vapour pressure established during lyophilisation).

[0120] Repetitive ice-annealing and freeze-texturising facilitates thegrowth of larger sheets of frozen solute throughout the gum matrix. Ineffect the sheets tend to provide channels to a point at or near thesurface of the gum This means that during lyophilisation, there is aminimal amount of channelling through the gum matrix from solventlocated in the centre of the gum pieces (the annealing already havingprovided channels). Thus, there is a minimal effect on the structure andintegrity of the gum during lyophilisation, since the sheet-likechannels easily open to the surface, and allow the solvent to escape andleave a marbling of dry solute (if present) throughout the gum matrix,which facilitates sustained release of the active ingredient substance.

[0121] Some compounds, particularly organic macromolecules, do not formcrystals when frozen, i.e. they behave as a glass and retain a certainamount of malleability even at very low temperatures. The inclusion ofsuch “glass formers” in the formulation will enhance the plasticity andductility of the frozen aggregate.

[0122] In comparison to cold milling and dry-mixing, the processdescribed gives improved sustained release characteristics and improvedgum texture. The difference is that dry mixing tends to coat thesurfaces of the gum particles preventing complete adhesion, this, causesthe gum to crumble and fall apart when chewed. The process describedherein creates discrete particles or sheets of solute within the gummatrix presenting clean gum surfaces, which re-adhere to each otherquite easily.

EXAMPLE 7

[0123] Comparison of Lysosyme-Containing Gums

[0124] Lysosyme is a constituent of egg white and purified extracts arereadily available for use in the food industry. The enzyme hasanti-microbial activity as it catalyses the hydration of murein inbacterial cell walls. The assay procedure involves measuring thespectrophotometric absorption change at 450 nm over time when a solutionof enzyme and Micrococcus lysodecticus is incubated at 30° C.

[0125] A first gum was prepared according to Example 6, but thecochineal was replaced by lysosyme powder added to the gum powder in anamount of 6% w/w.

[0126] A second gum was prepared using the hot melt procedure of Example2, and again replacing cochineal with a 6% w/w solution of lysosyme ingum powder.

[0127] The release rate of both gums was measured over time using achewing gum dissolution apparatus similar to that described by Rider etal., “Pharmaceutical Research”, Vol. 9, No. 2, 1992, and the results areplotted in FIG. 6, which shows the cumulative percentage release of thetotal load from each gum over a period of 16 minutes. In FIG. 6, theclosed circles represent the gum prepared according to the invention,while the open circles represent the hot melt gum.

[0128] The chewing gum dissolution apparatus is used to simulate therelease of active ingredient by a chewing action into a fluid bath. Theassay procedure described above is then used to measure the amount ofenzyme at different times. It can be seen from FIG. 6 that the gumaccording to the invention provided a significantly greater release thanfrom a conventionally prepared gum, and this release was sustained overa fifteen minute period.

[0129] It should be noted that although the Examples given abovedemonstrate the use of the method according to the invention in whichthe gum is initially frozen to −20° C., much lower initial temperaturesare contemplated when the procedure is carried out on a large scale.This is because if the gum is subjected to a temperature of e.g. −50° C.or −100° C., the increased temperature difference between the gum andthe surrounding environment will cause more rapid freezing of the gum,and hence will cause the entrapped liquid to form smaller crystals whichcan be manipulated using freeze-thaw texturising as required.

1. A method of manufacturing a chewing gum comprising the steps of: a)entrapping a liquid within a mass of gum; b) cooling the gum by anamount sufficient to freeze the entrapped liquid and thereby formentrapped frozen liquid crystals within the gum; and c) regulating thetemperature of the gum so as to manipulate the size and/or morphology ofthe frozen liquid crystals, and thereby manipulate the internalstructure of the gum to provide a gum having spaces therein of a platelike or sheet-like shape.
 2. A method according to claim 1, wherein stepa) comprises comminuting the gum to a particulate form and adding theliquid thereto.
 3. A method according to claim 2, wherein thecomminution of the gum is achieved by a process selected from jetmilling, homogenisation in a suspending liquid, and cryogenic milling.4. A method according to claim 1, wherein step a) comprises melting thegum, adding a liquid thereto, and forming an emulsion of the liquid inthe melted gum.
 5. A method according to any preceding claim, whereinstep b) comprises blast freezing the gum to a solid state.
 6. A methodaccording to any preceding claim, wherein the gum is frozen to atemperature which is more than 10° C. below the freezing point of saidliquid.
 7. A method according to any preceding claim, wherein step c)comprises regulating the temperature of the gum while maintaining theliquid in frozen form.
 8. A method according to claim 7, wherein step c)comprises bringing the gum to a temperature at which the crystalsundergo annealing.
 9. A method according to claim 8, wherein theannealing temperature to which the gum is brought in step c) issufficiently warm to cause the gum to exhibit plasticity withoutallowing the liquid to melt.
 10. A method according to claim 8 or 9,wherein the annealing temperature to which the gum is brought in step c)is within 5° C. of the melting point of the frozen liquid.
 11. A methodaccording to any one of claims 8-10, wherein the gum is maintained at anannealing temperature for not less than 2 hours.
 12. A method accordingto any one of claims 1-6, wherein step c) comprises thawing the liquidand re-freezing the liquid at least once.
 13. A method according toclaim 12, wherein step c) comprises thawing the liquid and re-freezingthe liquid at least three times.
 14. A method according to any precedingclaim, further comprising the step of: d) removing the liquid from thegum after step c).
 15. A method according to claim 14, wherein step d)comprises subjecting the gum to vacuum-assisted freeze drying.
 16. Amethod according to claim 14 or 15, wherein the liquid comprises asolvent in which a solute has been dissolved, and wherein the solvent isremoved to leave the solute entrapped in the gum.
 17. A method accordingto any one of claims 1-13, further comprising the step of; d′) sealingthe gum with the liquid intact either before or after thawing the gum.18. A method according to any preceding claim, wherein the gum ismechanically compressed during steps b) and c).
 19. A method accordingto any preceding claim, wherein the liquid added in step a) contains athermolabile substance.
 20. A method according to any preceding claim,where the liquid added in step a) comprises a homeopathic preparation.21. A method according to any preceding claim, wherein the liquid addedin step a) contains one or more purified constituents of egg.
 22. Amethod according to any preceding claim, wherein the liquid added instep a) contains one or more constituents having biological activitycharacteristic of human saliva.
 23. A method according to any precedingclaim, wherein the liquid added in step a) contains a herbal extract.24. A method according to claim 23, wherein the herbal extract isVaccinium myrtilis.
 25. A method according to claim 23, wherein theherbal extract is Melissa officianalis.
 26. A chewing gum comprising agum matrix having spaces within the gum matrix, characterised in thatthe size and/or morphology of the spaces is determined during themanufacture of the gum by a chance in the size and/or morphology ofcrystals of an entrapped frozen liquid present during manufacture, andin that the spaces have a plate-like or sheet-like shape due to theformation and growth of ice crystals during manufacture.
 27. A chewinggum according to claim 26, wherein the entrapped frozen liquid presentduring manufacture has been removed from the finished product.
 28. Achewing gum according to claim 27, wherein the spaces in the finishedproduct contain a residual material originally dissolved or suspended insaid liquid.
 29. A chewing gum according to claim 26, wherein the spacesin the finished product contain said liquid in thawed form.
 30. Achewing gum according to any one of claims 26-29, wherein the spaces areof an average size greater than the average maximum size of individualliquid volumes which can be incorporated in a gum matrix, due to the useof an annealing step which encourages crystal growth between adjacentcrystal structures.
 31. A chewing gum according to any one of claims26-30, wherein the entrapped frozen liquid present during manufacture isa liquid as defined in one of claims 19-25.
 32. A method ofmanufacturing a chewing gum, substantially as hereinbefore described andexemplified.
 33. A chewing gum substantially as hereinbefore describedwith reference to and as illustrated in FIGS. 4 and 5 of theaccompanying drawings.